Alzheimer's disease is a disease characterized by senile plaque formation and neurofibrillary tangles associated with nerve cell degeneration and nerve cell loss. At present, treatment of Alzheimer's disease is limited to symptomatic treatment with symptom-ameliorating agents represented by an acetylcholinesterase inhibitor, and no radical therapeutic agent for suppression of disease progression has been developed. Development of a method for controlling the etiology of the pathological condition is necessary for creation of a radical therapeutic agent for Alzheimer's disease.
The Amyloid β (hereinbelow, referred to as Aβ) protein, which is a metabolite of APP, is assumed to be largely associated with nerve cell degeneration and nerve cell loss, and further, the expression of symptoms of dementia (see, for example, Non Patent Literatures 1 and 2). The Aβ protein is mainly composed of Aβ40, which is composed of 40 amino acids, and Aβ42, which is composed of the 40 amino acids plus two additional amino acids at the C-terminus. The Aβ40 and Aβ42 are highly likely to aggregate (see, for example, Non Patent Literature 3), and are the main components of senile plaques (see, for example, Non Patent Literatures 3, 4, and 5). Moreover, mutation in the APP and presenilin genes observed in familial Alzheimer's disease is known to increase the Aβ40 and Aβ42 (see, for example, Non Patent Literatures 6, 7, and 8). Accordingly, a compound capable of reducing the production of Aβ40 and Aβ42 is expected to serve as an inhibitor or preventive drug for the progression of Alzheimer's disease.
Aβ is produced by cleavage of APP by a beta-site amyloid β precursor protein cleaving enzyme 1 (hereinbelow, referred to as BACE1 or beta-secretase), followed by further cleavage by gamma-secretase. In light of the above, with an aim to inhibit the production of Aβ, creation of a gamma-secretase inhibitor and a beta-secretase inhibitor has been attempted. Condensed ring compounds having a beta-secretase inhibitory action have been reported in literatures such as Patent Literatures 1 to 9 shown below, and especially, Patent Literatures 1 to 6 describe condensed aminodihydrothiazine derivatives and compounds having a BACE1 inhibitory activity.
The aforementioned Patent Literatures 1 to 5 and 7 to 8 describe a number of amide compounds represented by the following formulae, which are important compounds in the production of pharmaceutical products.
In the above formulas, R represents hydrogen, fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxyl, methoxymethyl, and the like.
The aforementioned compounds share, as a common partial structural motif, 5-(difluoromethyl)pyrazine-2-carboxamide, and these compounds are produced from the intermediate of 5-(difluoromethyl)pyrazine-2-carboxylic acid. As to the method for producing 5-(difluoromethyl)pyrazine-2-carboxylic acid (CAS Registry Number: 1174321-06-2), Production Example 17 of Patent Literature 1 describes that 5-(difluoromethyl)pyrazine-2-carboxylic acid can be produced by production steps such as ones illustrated in the following scheme using 5-methylpyrazine-2-carboxylic acid as a starting material.
